This application addresses broad Challenge Area (15) Translational Science and Specific Topic, 15-DK-111- The role of gastrointestinal surgical procedures in amelioration of type 2 diabetes. Bariatric surgery remains the most effective treatment for morbid obesity. In addition, bariatric surgery such as Roux-en Y Gastric Bypass causes the immediate resolution of type-II diabetes in the majority of patients (84%). This remarkable effect occurs well before any measureable weight loss. The mechanisms underlying this effect are unknown, but may involve stimulation of the lower intestine by chyme. Lower intestinal stimulation can be accomplished using a model called Ileal interposition. Interposition has been shown to improve glucose homeostasis in rat models of diabetes. Importantly, ileal interposition improves type-II diabetes in humans. With this model a portion of the lower intestine, or ileum, is relocated into a region within the jejunum and is therefore prematurely exposed to higher concentrations of nutrients and biliopancreatic secretions. Physiologically, interposition of the ileum results in dramatically enhanced secretion of two important ileal produced hormones, glucagon like peptide-1 (GLP-1) and peptide- YY (PYY), the former believed to be critical in the euglycemic effect. It is known that nutrient infusions into the gut will stimulate the secretion of gastrointestinal hormones like GLP-1 and PYY. However, the hypothesis is that the key anatomical aspect of bariatric procedures that result in the resolution of type-II diabetes is the exposure of the lower intestine to higher concentrations of bile salts. As mentioned above, the interposed ileum is exposed to high concentrations of biliopancreatic secretions. Bile uptake within the ileum and liver stimulate many factors critical for improved glucose and lipid homeostasis. Interestingly, other surgical procedures that result in delivery of elevated concentrations of bile to the lower intestine also lead to the immediate resolution of type-II diabetes. For example, by simply diverting bile flow to the lower intestine with a procedure called "Internal Biliary Diversion" diabetes is completely reversed within three days. In this proposal I will test the hypothesis that lower intestinal exposure to bile salts is sufficient for improving type-II diabetes in rats using Internal Biliary Diversion. Further, Internal Biliary Diversion will be compared with Ileal Interposition and the hormonal and bile-mediated factors will be examined to reveal the essential mechanisms by which these procedures improve glucose and lipid homeostasis. This work could lay the foundation for new treatments for type II diabetes in humans. PUBLIC HEALTH RELEVANCE: Obesity surgery is the most effective treatment for morbid obesity. Remarkably, most type-II diabetic patients who undergo obesity surgery experience complete resolution of their diabetes. The intriguing aspect of the remission of diabetes is that it occurs often immediately following surgery, prior to any substantial weight loss. This proposal aims to determine the role of bile as a component of the improved glucose metabolism following obesity surgery. The approach is novel in that two specialized surgical procedures that highlight the role of the lower intestine will be used. The findings have the potential to reveal novel treatments for patients with type-II diabetes and potentially improved surgical treatment of obesity and metabolic disorders.